Acute Cardiovascular Complications of COVID-19: A Systematic Review

Since the pandemic in 2019, coronavirus 2019 (COVID-19) has continued to be linked with a variety of organ systems and complications. While it is generally considered a respiratory disease, its link with the heart is widely discussed in the literature. This article focuses on the acute cardiovascular complications of COVID-19 and the possible predictors of these complications. Our study included 97 articles (58 case reports, eight case series, 23 retrospective cohort studies, five prospective cohort studies, and three cross-sectional studies). Several mechanisms have been proposed to explain COVID-19-induced cardiovascular complications, with cytokine-induced inflammation and direct cardiac damage noted as the significant focus. Patients with underlying cardiovascular complications such as hypertension and diabetes were noted to be at increased risk of acute cardiovascular complications, as well as an increased risk of severe disease and death. Also, acute myocardial infarction and arrhythmias were two of the most common acute cardiovascular complications noted in our review. Other acute cardiovascular complications are myocarditis, takotsubo syndrome, acute thromboembolic events, and pericardial complications. This article provides an updated review of acute cardiovascular complications of COVID-19, its pathogenesis, and risk stratification and emphasizes the need for high suspicion in patients with underlying cardiovascular risk factors.


Introduction And Background
The coronavirus disease 2019 (COVID-19) remains one of the most fatal pandemics the world has experienced recently. The emergence of COVID-19 was first described in a group of patients presenting in Wuhan, China, with severe pneumonia-like symptoms (first wave). In this subset of patients, a novel virus called the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was isolated from the lower respiratory tract samples [1]. Since then, at least five outbreak waves have been described [2]. The first wave presented majorly with respiratory symptoms, while gastrointestinal symptoms were added during the second wave, and peripheral neurological manifestations replaced the gastrointestinal symptoms in the third wave. Central nervous system manifestations were added to the fourth and fifth waves [2]. However, key to note that as the pandemic wore on, morbidity and mortality have continued to increase, with cardiovascular complications a peak of the group. So far, in the United States, there have been 103,499,382 confirmed cases and 1,117,856 confirmed deaths from COVID-19-related complications [3]. Although most presentations have been related to varying severity of upper and lower respiratory system involvement, evidence of extrapulmonary manifestations remains equally common [4,5]. Several cardiac complications, such as acute cardiac injury, heart failure, arrhythmias, cardiogenic shock, and right ventricular dysfunction, have been documented in current literature, with significant impacts on outcomes reported [6]. Direct myocardial cell injury (via the ACE2 receptors), overwhelming systemic inflammation, hypoxic state, catecholamines storm, cytokines release, and electrolyte derangements have been suggested as the possible link between COVID-19 and cardiovascular complications [7]. Literature has also noted an increased risk of cardiovascular events in patients with pre-existing cardiovascular diseases such as hypertension and diabetes. This systematic review aims to describe the acute cardiovascular complications of COVID-19, the outcome reported in the literature so far, and the associated risk factors, such as in patients with existing co-morbidities. This review article also aims to provide awareness of cardiovascular events in patients with COVID-19, promoting the suspicion of cardiac events for early identification and intervention.

Search Strategy
We searched databases (PubMed/MEDLINE, Google Scholar, Wiley Online Library) using free-text terms in the title and appropriate Medical Subject Headings (MeSH) terms-COVID-19 and Acute cardiovascular complications. We collected all records into one library, with 364 results found. We exported the final list into a Word document file to remove duplicates. All search results, including titles and abstracts of retrieved articles, were then screened to assess for eligibility which was independently reviewed and agreed upon by team consensus. Finally, we obtained a full-length manuscript for all intended studies for review, which was 97 articles (58 case reports, 8 case series, 23 retrospective cohort studies, 5 prospective cohort studies, and 3 cross-sectional studies). The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flowchart shown in Figure 1 below further highlights the process used in our articles selection.

Inclusion and Exclusion Criteria
We assessed primary studies of any design type, including randomized clinical trials, case-control, prospective and retrospective cohort studies, case series, and reports published between January 2020 and September 2022, evaluating acute cardiovascular complications in COVID-19 patients and associated clinical risk factors. No restrictions were made with regard to the age, sex, race, ethnicity, nationality, or vaccination status of the individuals.
We included studies that have indexed COVID-19 disease as confirmed by rt-PCR. Acute cardiovascular complications are cerebrovascular disorders, dysrhythmias, ischemic and non-ischemic heart disease,

Results
Electronic literature searches identified 364 articles in total. We excluded systematic reviews and metaanalyses; international expert recommendations; studies with non-human subjects or in vitro studies; studies with data not reliably extracted, duplicate, or overlapping data; abstract-only papers as preceding papers, conference, editorial, and author response theses and books; and articles without available full text. We selected 97 articles for full-text review pertaining to our study.
Below are tables (Tables 1-7) showing articles reporting each of our primary outcome data: Acute cardiovascular complications of COVID.

COVID-19 and Patients With Underlying Cardiovascular Disease or Cardiovascular Disease Risk Factors
Literature has shown that patients with pre-existing cardiovascular disease or cardiovascular disease risk factors are at risk for more severe COVID-19 complications. In a study by Shao et al., hypertension was noted in approximately 55.6% of COVID-19 cases [89]. In a study by Cao et al., hypertension was found in 55% of ICU patients with COVID-19 [90]. In a study by Chen et al., 48% of deceased patients from COVID-19 had underlying hypertension, while only 24% of the recovered patients had hypertension [91]. Also, in a study by Zhou et al., hypertension was found in 23% versus 48% (P=0.0008) of survivors and non-survivors, respectively [92]. Also, hypertension (38%, P = 0.01) was noted to be the most common comorbidity found in patients who developed acute cardiac injury during hospital stay [93].
In a study by Chen et al., underlying cardiovascular disease was more common in patients who died versus those that survived (14% versus 4%) [91]. Zhang et al. also noted that underlying cardiovascular disease was present in severe COVID-19 presentations (23.6%) versus mild COVID-19 manifestations (5.4%, P < 0.001) [94]. In a study by Guo et al., patients with underlying cardiovascular disease (such as coronary heart disease, cardiomyopathy, underlying arrhythmia, and hypertension) and developed cardiac injury had higher mortality rates at up to 69.44% versus 13.3% in patients without underlying cardiovascular disease [95].
The above findings emphasize the link between COVID-19 and underlying cardiovascular disease in predicting the severity of COVID-19 outcomes. Patients with pre-existing cardiovascular disease or cardiovascular disease risk factors have an increased rate of severe presentation, critical care unit admission, and higher mortality rates.

Pathophysiology
Several direct and indirect mechanisms have been used to explain the possible link between COVID-19 and cardiovascular complications (Figure 2). A complex interaction between the virus, the host responses, and underlying cardiovascular comorbidities characterize the link. Cardiac injury results from an interplay between the virus and host cells [96]. Studies from autopsy reports have also shown macrophage and lymphocytic infiltration, as well as viral fragments in the endothelium of cardiac vessels; however, no viral replication was noted [97]. Also, enormous inflammatory changes have been reported through cytokine storms and dysregulation of the host immune response [98]. Hypoxia from COVID-19-related respiratory failure has also led to an oxygen supply/ demand mismatch, further increasing the risk for myocardial infarction [99]. There is also a possible imbalance between the pro-and anti-inflammatory system resulting in an erratic inflammatory response activation, including catecholamine and IL-6 release, and the consequent inability of the host to limit inflammation [100,101]. This further leads to overwhelming inflammation. The release of catecholamines increases heart rate and oxygen demand, which is detrimental to cardiac function. The overwhelming release of inflammatory markers (cytokines and chemokines) also leads to endothelial dysfunction, spasms of coronary arteries, and thrombi formation, which to a greater extent reduces blood supply to the heart. The above mechanisms: hypoxia and inflammation, leading to mitochondrial dysfunction, and alterations of calcium channels leading to impairment in myocytes' contractility activity [102]. Hypercoagulation through enormous inflammation has also been noted in COVID-19 patients, potentially responsible for some cardiac injuries, such as occlusive thrombus formation [103]. Drug-related cardiac injuries have also been reported, especially QT prolongation from medications (hydroxychloroquine, azithromycin) used to treat COVID-19 infection [104].

Type 1 Myocardial Infarction
One of the most evident/common/reported complications of COVID-19 infection is acute myocardial infarction, with several cases of COVID-19-related myocardial infarction reported in the literature, as noted in Table 1. Most of the patients reported were symptomatic with typical angina symptoms. Hypertension, diabetes, a history of coronary artery disease, and smoking were these patients' most commonly reported comorbidities [8, 11, 12-14, 17-20, 23-26, 29]. However, some cases were reported in patients without medical history [9,10]. Although this complication was more common in patients older than 50 years, there were a few cases in the younger population, especially those with severe COVID-19 infection [9,10]. At least two coronary dissection-induced myocardial infarction cases have also been reported; however, this was more common in patients with no documented medical history [34,35]. Possible pathophysiology is secondary to the overwhelming release of inflammatory markers (cytokines and chemokines), which leads to endothelial dysfunction, coronary artery spasm, and thrombosis [99]. Also, the release of catecholamines increases heart rate and oxygen demand, which is detrimental to cardiac function. The increased risk of hypercoagulation in severe cases of COVID-19 is another mechanism that has been suggested [103]. There were also varying outcomes, with better outcomes in younger patients with no reported past medical history [9,10]. Diabetes, hypertension, and smoking were the common comorbidities in patients who died. Early treatment and intervention remain effective in preventing fatal outcomes in patients with COVID-19induced acute myocardial infarction.

COVID-19-Induced Heart Failure, Cardiogenic Shock
Acute heart failure is another documented cardiovascular complication of COVID-19 infection, as noted in Table 2. This is likely secondary to hypoxia and inflammation, leading to mitochondrial dysfunction and alterations of calcium channels leading to impairment in myocytes' contractility [102]. About 23% of 191 inpatients from Wuhan, China, developed new-onset heart failure [92]. Acute heart failure was more common in patients with pre-existing cardiovascular disease and associated with increased mortality [16,33,36,38,39]. However, there was at least one case of heart failure in a patient without documented past medical history [48]. A recent retrospective study also noted an increased risk of acute heart failure in diabetic patients (25.2%) versus non-diabetics (5.6%) which could suggest a possible association [16]. A case of right ventricular dysfunction was also reported, with a potentially worse outcome [39].

COVID-19-Induced Myocarditis
Myocarditis is an inflammatory condition that involves the heart muscles (myocardium), leading to a myriad of clinical manifestations: chest pain, irregular heartbeats, and difficulty with breathing. Like other viruses, myocarditis is a commonly reported cardiac complication of COVID-19, with several cases reported in the literature, as reported in Table 3. Myocarditis was more frequently seen in patients with a severe presentation of COVID-19, with an increased mortality risk. The first case of myocarditis was in a 63-yearold male with no significant past cardiac medical history who was noted to have elevated interleukin-6 (IL-6) and myocardial injury markers such as troponin I, who subsequently died [43]. A retrospective study by Finn et al. reported a mortality rate as high as 61% in patients with acute myocarditis [46]. Although more common in patients with a documented medical history, there were several cases of myocarditis in patients without significant medical history, especially in the younger population [40,42,45,47]. Patients without underlying medical problems were also associated with better outcomes [19,40,42,45]. A study also showed a possible association between diabetes and the risk of myocarditis in COVID-19 patients, with 36.6% of diabetic patients developing acute myocarditis versus 15.5% of non-diabetics [16]. Increased mortality was also observed in patients with fulminant myocarditis, often complicated by pericarditis, pericardial effusion, and cardiac tamponade [41]. Ismayl et al. also reported a possible progression to cardiogenic Shock in fulminant cases [41]. The potential link with cardiogenic Shock involves myocardial inflammation leading to an abrupt decrease in cardiac contractility, inotropic deficit, and subsequent increase in filling pressures and diffuse myocardial edema. Patients who recovered were those that responded well to anti-inflammatory agents such as colchicine, steroids, and intravenous immunoglobin (IVIG). This finding could suggest an inflammatory pathway as a cause of this presentation [42]. The main mechanisms discussed were cardiomyocyte destruction due to viral entry, cytokine release syndrome, and hyperinflammation [42].

COVID-Induced Pericarditis, Pericardial Effusion, and Cardiac Tamponade
Alongside type 1 myocardial infarction, pericardial-related complications are among the most reported cardiovascular complications of COVID-19 infection, as noted in Table 4. As with other cardiovascular complications, pericardial-related complications were more common in older patients and patients with existing cardiovascular comorbidities. However, at least two cases were noted in the younger population, both presenting with severe complications -massive hemorrhagic pericardial effusion and myopericarditis, respectively and associated with mortality [54,59]. The recovered patients responded well to antiinflammatory agents, which suggests underlying inflammation as the cause of this complication.

COVID-19-Induced Thromboembolism
Hypercoagulation through enormous inflammation has also been noted in COVID-19 patients, as noted in Table 5, potentially responsible for some cardiac injuries, such as occlusive thrombus formation [103]. The possible mechanism involves both direct (micro vasculitis viral damage) and indirect mechanisms (through downregulation of ACE2 receptor, hypoxia, and disseminated intravascular coagulopathy) and even from prolonged immobilization in severe COVID-19 cases [103]. There are at least nine case reports on COVIDinduced thrombosis; common to these patients was existing medical history of diabetes, which could suggest a positive association [23,60,61,63,64,[67][68][69][70]. A significantly elevated D-Dimer level is also common among these patients. Among the reported complications were deep venous thrombosis and acute pulmonary embolism, which appears to be the most common -at least two cases of critical limb ischemia leading to amputation [60,67] [68]. A potentially severe complication of COVID-19-induced thromboembolism is myocardial infarction, reported in at least three case reports [60,69,70]. There were also at least three cases of mortality from the nine cases reported [62,67,70]. Cases with critical limb ischemia also ended with amputation [61,67]. This suggests the possible need for anticoagulation in patients with severe presentations of COVID-19 and significantly elevated D-Dimer levels due to the hypercoagulability risk.

COVID-19-Induced Takotsubo Syndrome
Takotsubo syndrome has been identified as one of the most common cardiac complications of COVID-19, as noted in Table 6. In the cases reported, the patients presented with chest discomfort, elevated troponins, and EKG alterations. In the case series by Arroyo-Rodriguez et al., four of the cases demonstrated classic apical ballooning, with one patient showing atypical presentation with anterolateral akinesia [72]. Coronary angiography was done in 4/5 cases to rule out acute coronary syndrome, which came back negative.
Takotsubo syndrome was also found in older patients over 65; however, there was a case of a 53-year-old patient with stage III chronic kidney disease (CKD) [75]. A common complication of Takotsubo syndrome identified was a cardiogenic shock, which was also associated with an increased risk of mortality [72,75]. In the case series by Arroyo-Rodriguez et al., there was mortality in 4/5 cases, contradictory to other reports with a survival rate of 91.6% [72]. A possible association was the severity of the COVID-19 infection, with increased mortality noted in patients that are mechanically ventilated due to acute respiratory distress syndrome (ARDS), older patients, need for vasopressors, underlying renal failure, and underlying heart failure [72]. The suggested link between COVID-19 and Takotsubo syndrome is an overactive immune response due to cytokine storm, sympathetic drive, and microvascular dysfunction [72]. This is similar to the exact mechanism identified in other cardiac complications of COVID-19.

COVID-19-Induced Arrhythmias
Alongside type 1 myocardial infarction, arrhythmias are a commonly seen cardiac complication and one of the early clinical manifestations of COVID-19, reported in the literature as noted in Table 7. Possible suggested etiologies are hypoxia, inflammatory cytokine storm, and drug interactions. In multiple studies on the cardiac complications of COVID, dysrhythmias/arrhythmias were the most common complication identified [22,79]. New-onset atrial fibrillation appears to be the most frequent arrhythmia reported. In a recent retrospective study by Khawaja et al.,19.1% of COVID-19 patients developed new-onset atrial fibrillation [81]. This is similar to another retrospective study that revealed new-onset atrial fibrillation in 12.7% of the COVID-19 patients studied. Also, in a study by Mónica et al., 6.5% of the patients developed new-onset atrial fibrillation [21].
Conduction abnormalities were another commonly reported arrhythmia [11,23,77,84,85,88]. In a case by Lalani et al., 45.6% of 730 patients developed prolonged QTc interval, while 24.2% developed sinus tachycardia [11]. A possible explanation is using drugs such as azithromycin and hydroxychloroquine in COVID-19 patients [104]. Wide complex tachyarrhythmias were also reported, with cases of ventricular tachycardia -both sustained and non-sustained, ventricular fibrillation [77,83]. Patients with underlying cardiovascular diseases were also noted to be at an increased risk of new-onset arrhythmias. In a study by Abe et al., 12.7% had new-onset atrial fibrillation versus 1.4% of non-diabetics [16].
Bradycardia is a crucial possible complication of COVID-19 infection that is frequently reported in the literature [23,77,82]. In a case series by Kaeley et al., 25% of patients developed a new-onset right bundle branch block [23]. The emergence of bradyarrhythmias in COVID-19 patients has also been suggested as a possible complication of an extreme cytokine storm with the potential for more serious cardiac complications [100,101]. Guo et al., in a recent study, correlated an increase in N-Terminal proB-type Natriuretic Peptide (NP-proBNP) level with the development of malignant arrhythmias, which suggests a possible relationship between acute myocarditis and arrhythmias [95]. Therefore, it is essential to consider myocarditis in patients with a new development of tachyarrhythmias and increased cardiac biomarkers in patients with COVID-19.

Conclusions
Acute cardiac injury is one of the most common complications of COVID-19 infection. Patients with acute cardiovascular complications appear to have pre-existing cardiovascular disease, older age group, and those with severe COVID-19 presentation. These groups also appear to have an increased risk of mortality. Type 1 myocardial infarction and arrhythmias appear to be the most common acute cardiac complication of COVID-19 infection, with hypertension and diabetes noted as one of the most common co-morbidities in these patients. This article provides an updated review of the acute cardiac complications of COVID-19. It also guides the suspicion of providers and serves as a future template for further research on each of the acute cardiac complications of COVID-19 infection, as well as providing support for implementing preventive strategies for patients at risk. Further studies are needed to evaluate the long-term cardiac complications of COVID-19.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.